The art of radiochemistry has found many applications in the fields of boiological research and medical diagnosis. It is well known that certain radioactive preparations, when introduced into a biological system, will localize in specific organs, tissues or skeletal material. With radiation detecting devices, it is then possible to visualize these target areas, and thereby monitor the functioning of certain organs, for example, the kidney and liver, or to diagnose aberrations or pathological conditions existing in certain tissues, for example, the skeleton.
The metastable isotope Tc-99m is particularly desirable for use in radiopharmaceutical preparations because of its unique combination of nuclear properties. This nuclide has a high specific activity (99 percent gamma radiation at 140 keV), which makes possible the visualization of deep organs, yet the radiation is easily collimated. Tc-99m also has a conveniently rapid rate of decay (6 hour half-life) which is ideal for most diagnostic purposes. The absence of beta emissions from Tc-99m reduces the radiation hazard to the patient, and although Tc-99m's decay product Tc-99 is a beta emitter, it has a very long half-life, and, thus, radiation from residual amounts of this material is of little consequence to the patient. In recent years, Tc-99m has become readily available to laboratories through the use of a molybdenum-99 (Mo-99) generator from which Tc-99m is obtained as a radioactive decay product.
Although Tc-99m would appear to be an ideal material for use in radiopharmaceuticals, a problem arises in finding suitable carriers of ligands which will form stable complexes with the nuclide and impart to it the desired organ specificity. Complexes of Tc-99m must also exhibit minimal toxic side effects and be safely eliminated from the body.
A number of complexes of Tc-99m have been introduced in recent years which have predictable stability and organ specificity. Known complexes of Tc-99m are primarily designed for the study of one organ system. For example, Tc-99m complexed with pencillamine and acetazolamide, described in U.S. Pat. No. 3,743,913, is primarily useful as a kidney scanning agent. Tc-99m-sulfur colloid complex, described in British Pat. No. 1,305,035, is designed for liver scanning; and Tc-99m-labeled polyphosphate, described in Radiology 102: 701-704, Mar. 1972, is generally employed as a bone imaging agent.
Several currently available Tc-99m complexes for bone imaging utilize phosphorus-containing ligands. These ligands are primarily inorganic compounds such as the polyphosphates referred to above. However, U.S. Pat. No. 3,735,001 describes a Tc-99m complex with the organic phosphorus-containing ligand ethane-1-hydroxy-1,1-diphosphonate.
In contrast to the single-organ specific complexes of the prior art, the present invention provides a multi-organ diagnostic system utilizing monophosphonic acids as complexing agents for Tc-99m. By slight chemical variation of the complexing agent, the complexes of the invention can be directed to the kidney, liver or skeleton. These complexes exhibit superior organ specificity over many known imaging agents. They are stable chemically and biologically, of low toxicity, and are safely eliminated from the body. In addition, the complexes of the present invention are water soluble and easily prepared. Their preparation does not require strict adherence to stoichiometric relationships among components or rigorous control of pH, which are problems commonly encountered in the preparation of known Tc-99m complexes.